Background: Despite many advances in the field of AIDS research, a treatment that eradicates the infection remains elusive. A key obstacle to the development of a cure for HIV is an incomplete understanding of the cellular and anatomic nature of viral reservoirs in the setting of successful ART. To address this gap in our understanding, we developed a model of autologous hematopoietic stem cell transplantation (aHSCT) in SIV-infected, ART-treated rhesus macaques (RM) to interrogate the origin of the SIV reservoir.
Methodology: This pilot study included three SIV-infected RM who received aHSCT and three SIV-infected control RM. The transplant procedure involved pre-infection G-CSF mobilization of CD34+ HSC followed by leukapheresis and cryopreservation of collected cells. All RM were then infected i.v. with RT-SHIV. Four weeks post-infection a potent ART regimen including PMPA, FTC, Efavirenz and Raltegravir was initiated. The three experimental RM received total body irradiation (TBI) followed by infusion of the HSC collected pre-infection. ART was interrupted 40 to 80 days post-transplant. Immunophenotyping of PBMC and measurements of plasma SIV RNA and PBMC SIV DNA levels were collected throughout the study. Multiple tissues described as potential virus reservoirs were collected at necropsy for virologic analyses.
Results: As expected, the ART regimen reduced plasma SIV RNA levels to below 100 copies/ml in all six SIV-infected RM. TBI was myeloablative as measured by circulating platelet, white blood cell, and lymphocyte counts and, following aHSCT, engraftment was successful in all three transplanted RM. A rapid viral rebound was observed in plasma in the non-transplanted control RM as early as one week post-ART interruption. Despite TBI and transplant with pre-infection HSC, plasma SIV RNA rebound was also observed post-ART interruption in two out of three transplanted RM. In contrast, no SIV RNA was detected in the plasma of one transplanted RM at week two post-ART interruption. Furthermore, no SIV DNA was detected in the PBMC of this transplanted animal. However, despite the lack of viral rebound in plasma in this transplanted RM, further analysis of various tissue sites revealed the presence of SIV DNA in spleen and lymph nodes, but not in the gastrointestinal tract.
Conclusions: To the best of our knowledge, this model of SIV/HSCT has never been attempted before. SIV infection followed by aHSCT in virallysuppressed ART-treated RM allows for critical assessment of hematopoietic and non-hematopoietic HIV/SIV reservoirs. Early evidence from this study suggests that non-hematopoietic reservoirs contribute to HIV/SIV persistence. The results of this work may be translated into novel HIV cure strategies.